Intracameral sustained release therapeutic agent implants

ABSTRACT

Described herein are intracameral implants including at least one therapeutic agent for treatment of at least one ocular condition. The implants described herein are not anchored to the ocular tissue, but rather are held in place by currents and gravity present in the anterior chamber of an eye. The implants are preferably polymeric, biodegradable and provide sustained release of at least one therapeutic agent to both the trabecular meshwork and associated ocular tissue and the fluids within the anterior chamber of an eye.

CROSS-REFERENCE

This application is a continuation of U.S. application Ser. No.15/362,197, filed on Nov. 28, 2016, which is a continuation of U.S.application Ser. No. 14/746,438, filed on Jun. 22, 2015, now issued asU.S. Pat. No. 9,504,696, which is a divisional of U.S. application Ser.No. 14/031,657, filed on Sep. 19, 2013, now issued as U.S. Pat. No.9,061,065, which is a divisional of U.S. application Ser. No.13/011,467, filed on Jan. 21, 2011, now issued as U.S. Pat. No.8,647,659, which claims the benefit of U.S. Provisional PatentApplication Ser. No. 61/297,660, filed on Jan. 22, 2010, the entiredisclosure of which is incorporated herein by this specific reference.The entire disclosure of the aforementioned patent applications areincorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to intracameral sustained release implantsand methods of making and using the same.

SUMMARY

Described herein are intraocular systems and methods for treating ocularconditions. In particular, local administration of a sustained releasetherapeutic agent delivery system to the anterior chamber and/or toanterior vitreous chamber of the eye to treat aqueous chamber elevatedintraocular pressure is described.

Further, described herein are methods for treating an ocular conditioncomprising the steps of: providing at least two biodegradable sustainedrelease implants containing at least one therapeutic agent; implantingthe at least two biodegradable sustained release implants into theanterior chamber of an eye; and treating the ocular condition, whereinthe at least two biodegradable sustained release implants release about100 ng per day of the at least one bioactive agent for a period greaterthan about 1 month.

Further still, described herein are methods for treating glaucoma in aneye comprising the steps of: providing at least two biodegradablesustained release implants containing at least one therapeutic agent;implanting the at least two biodegradable sustained release implantsinto the anterior chamber of the eye; allowing a sufficient time for theat least two biodegradable sustained release implants to settled out inthe inferior angle; allowing a sufficient time for the at least twobiodegradable sustained release implants to release the at least onetherapeutic agent; and treating glaucoma, wherein the at least twobiodegradable sustained release implants release about 100 ng per day ofthe at least one bioactive agent for a period greater than about 1month.

In one embodiment, the ocular condition is glaucoma and/or elevatedintraocular pressure. The sustained release implants can release about70% of the at least one therapeutic agent over the first month. In someembodiments, the at least one therapeutic agent can comprise about 30%of the at least two biodegradable sustained release implants and isselected from the group consisting of latanoprost, bimatoprost andtravoprost and their salts, esters and prodrugs.

In another embodiment, the at least two biodegradable sustained releaseimplants comprise about 5% to about 70% poly(D,L-lactide). In otherembodiments, the at least two biodegradable sustained release implantscomprise about 5% to about 40% poly(DL-lactide-co-glycolide). In yetother embodiments, the at least two biodegradable sustained releaseimplants comprise about 5% to about 40% polyethylene glycol.

In still other example embodiments, the at least two biodegradablesustained release implants comprise about 30% therapeutic agent, 65%poly(D,L-lactide), and 5% polyethylene glycol or about 20% therapeuticagent, 55% poly(D,L-lactide), 10% poly(DL-lactide-co-glycolide), and 5%polyethylene glycol.

The implants themselves can be inserted into the ocular tissue using anappropriate applicator. Once implanted, the at least two biodegradablesustained release implants can settle out in the inferior angle within24 hours of implanting within the anterior chamber.

In one embodiment, the the sufficient time for the at least twobiodegradable sustained release implants to release the at least onetherapeutic agent is greater than about 42 days.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates the two different pathways for aqueous humor outflowfrom the anterior chamber both located in the iridocorneal angle.

FIG. 2 illustrates the placement of an implant as described herein atthe location of aqueous humor outflow from the anterior chamber.

FIG. 3 illustrates the currents located within the anterior chamber ofan eye as well as a possible location of an implant or implants asdescribed herein.

FIG. 4 graphically illustrates a release profile of implants of thepresent description.

FIG. 5 graphically illustrates a release profile of implants of thepresent description.

FIG. 6 illustrates the placement of an implant according the presentdescription.

DEFINITION OF TERMS

“About” means plus or minus ten percent of the number, parameter orcharacteristic so qualified.

“Biodegradable polymer” means a polymer or polymers which degrade invivo, and wherein erosion of the polymer or polymers over time occursconcurrent with or subsequent to release of the therapeutic agent. Theterms “biodegradable” and “bioerodible” are used interchangeably herein.A biodegradable polymer may be a homopolymer, a copolymer, or a polymercomprising more than two different polymeric units. The polymer can be agel or hydrogel type polymer, polylactic acid orpoly(lactic-co-glycolic) acid or polyethylene glycol polymer or mixturesor derivatives thereof.

“Ocular condition” means a disease, ailment or condition which affectsor involves the ocular region. Broadly speaking, the eye includes theeyeball and the tissues and fluids which constitute the eyeball, theperiocular muscles (such as the oblique and rectus muscles) and theportion of the optic nerve which is within or adjacent to the eyeball.

An anterior ocular condition is a disease, ailment or condition whichaffects or which involves an anterior (i.e. front of the eye) ocularregion or site, such as a periocular muscle, an eye lid or an eye balltissue or fluid which is located anterior to the posterior wall of thelens capsule or ciliary muscles. Thus, an anterior ocular conditionprimarily affects or involves the conjunctiva, the cornea, the anteriorchamber, the iris, the posterior chamber (behind the retina but in frontof the posterior wall of the lens capsule), the lens or the lens capsuleand blood vessels and nerve which vascularize or innervate an anteriorocular region or site.

Thus, an anterior ocular condition can include a disease, ailment orcondition, such as for example, aphakia; pseudophakia; astigmatism;blepharospasm; cataract; conjunctival diseases; conjunctivitis; cornealdiseases; corneal ulcer; dry eye syndromes; eyelid diseases; lacrimalapparatus diseases; lacrimal duct obstruction; myopia; presbyopia; pupildisorders; refractive disorders and strabismus. Glaucoma can also beconsidered to be an anterior ocular condition because a clinical goal ofglaucoma treatment can be to reduce a hypertension of aqueous fluid inthe anterior chamber of the eye (i.e. reduce intraocular pressure).

A posterior ocular condition is a disease, ailment or condition whichprimarily affects or involves a posterior ocular region or site such aschoroid or sclera (in a position posterior to a plane through theposterior wall of the lens capsule), vitreous, vitreous chamber, retina,optic nerve (i.e. the optic disc), and blood vessels and nerves whichvascularize or innervate a posterior ocular region or site.

Thus, a posterior ocular condition can include a disease, ailment orcondition, such as for example, acute macular neuroretinopathy; Behcet'sdisease; choroidal neovascularization; diabetic uveitis; histoplasmosis;infections, such as fungal or viral-caused infections; maculardegeneration, such as acute macular degeneration, non-exudative agerelated macular degeneration and exudative age related maculardegeneration; edema, such as macular edema, cystoid macular edema anddiabetic macular edema; multifocal choroiditis; ocular trauma whichaffects a posterior ocular site or location; ocular tumors; retinaldisorders, such as central retinal vein occlusion, diabetic retinopathy(including proliferative diabetic retinopathy), proliferativevitreoretinopathy (PVR), retinal arterial occlusive disease, retinaldetachment, uveitic retinal disease; sympathetic opthalmia; VogtKoyanagi-Harada (VKH) syndrome; uveal diffusion; a posterior ocularcondition caused by or influenced by an ocular laser treatment;posterior ocular conditions caused by or influenced by a photodynamictherapy, photocoagulation, radiation retinopathy, epiretinal membranedisorders, branch retinal vein occlusion, anterior ischemic opticneuropathy, non-retinopathy diabetic retinal dysfunction, retinitispigmentosa, and glaucoma. Glaucoma can be considered a posterior ocularcondition because the therapeutic goal is to prevent the loss of orreduce the occurrence of loss of vision due to damage to or loss ofretinal cells or optic nerve cells (i.e. neuroprotection).

“Ocular region” or “ocular site” means any area of the eyeball,including the anterior and posterior segment of the eye, and whichgenerally includes, but is not limited to, any functional (e.g., forvision) or structural tissues found in the eyeball, or tissues orcellular layers that partly or completely line the interior or exteriorof the eyeball. Specific examples of areas of the eyeball in an ocularregion include the anterior (aqueous) chamber, the posterior chamber,the vitreous cavity, the choroid, the suprachoroidal space, theconjunctiva, the subconjunctival space, the episcleral space, theintracorneal space, the epicorneal space, the sclera, the pars plana,surgically-induced avascular regions, the macula, and the retina.

“Sustained release” or “controlled release” refers to the release of atleast one therapeutic bioactive agent, or drug, from an implant at apredetermined rate. Sustained release implies that the therapeuticbioactive agent is not released from the implant sporadically in anunpredictable fashion and does not “burst” from the implant upon contactwith a biological environment (also referred to herein as first orderkinetics) unless specifically intended to do so. However, the term“sustained release” as used herein does not preclude a “burstphenomenon” associated with deployment. In some example embodimentsaccording to the present description an initial burst of at least onetherapeutic agent may be desirable followed by a more gradual releasethereafter. The release rate may be steady state (commonly referred toas “timed release” or zero order kinetics), that is the at least onetherapeutic agent is released in even amounts over a predetermined time(with or without an initial burst phase) or may be a gradient release.For example, sustained release can have substantially no fluctuations intherapeutic agent delivery as compared to topical administration.

“Therapeutically effective amount” means level or amount of agent neededto treat an ocular condition, or reduce or prevent ocular injury ordamage without causing significant negative or adverse side effects tothe eye or a region of the eye. In view of the above, a therapeuticallyeffective amount of a therapeutic agent, such as a latanoprost, is anamount that is effective in reducing at least one symptom of an ocularcondition.

DETAILED DESCRIPTION

Described herein are intracameral implants including at least onetherapeutic agent. The implants described herein are placed in theanterior chamber of an eye, but are not anchored to the ocular tissue.Rather, the implants are held in place by currents and gravity presentin the anterior chamber of the eye. The implants are preferablypolymeric, biodegradable and provide sustained release of at least onetherapeutic agent to both the trabecular meshwork (TM) and associatedocular tissues, and the fluids within the anterior chamber of theimplanted eye.

Direct intracameral or anterior intravitreal administration of sustainedrelease implants or therapeutic agent delivery systems, as set forthherein, are effective in treating an array of ocular conditions outlinedherein. On such condition is glaucoma characterized by elevatedintraocular pressure which can be treated as described herein bybypassing the robust scleral drug clearance mechanisms (e.g. topicaldrops).

Intraocular pressure (IOP) variation appears to be an independent riskfactor for glaucomatous damage. Conventional therapy for treating ocularhypertension or glaucoma is the use of anti-hypertensive topicalophthalmic drops to lower the IOP. Unfortunately, bolus dosing withtopical ophthalmic drops results in anterior chamber therapeutic agentlevels with peak and trough levels that results in variability of IOPcontrol over time. This fluctuation in IOP can result in glaucomatousfield progression, especially in patients with advanced glaucoma.Addressing this unmet need in patients with ocular hypertension orglaucoma that require medical therapy, are the sustained-releaseintracameral implants described herein. The implants can establish lowfluctuations of the IOP throughout the day and the night when topicaldrops are inconvenient. A nocturnal IOP spike occurs between 11 pm and 6am in patients with open angle glaucoma, and this may contribute toprogressive visual field loss in some patients. The additionallimitation of topical therapy is the lack of steady state drugconcentrations in the anterior chamber with bolus dosing not controllingnocturnal IOP elevations in a number of patients. The implants describedherein establish low fluctuations of the IOP throughout the night aswell, thereby alleviating the complications of topical administration inthe nighttime hours.

Non-compliance with a medical regimen containing one or more topical eyedrops to treat ocular hypertension or glaucoma occurs in over 50% ofpatients and this may contribute to IOP fluctuation during the day whendrops are not used on a regular schedule. The implants described hereindo not require such compliance, and are therefore more patient friendly.

Described herein are intracameral sustained release therapeutic agentimplants that provide continuous release of the therapeutic agentthereby avoiding the peak and trough therapeutic agent levels that occurin the aqueous humor with topical dosing. The steady state drugconcentrations achieved in the aqueous humor with the implants describedherein can significantly lower the IOP fluctuation during the day andnight unlike conventional topical administration of drugs.

The anterior and posterior chambers of the eye are filled with aqueoushumor, a fluid predominantly secreted by the ciliary body with an ioniccomposition similar to the blood. The function of the aqueous humor istwo-fold: 1) to supply nutrients to the avascular structures of the eye,such as the lens and cornea, 2) maintain IOP within its physiologicalrange. Maintenance of IOP and supply of nutrients to the anteriorsegment are factors that are critical for maintaining normal visualacuity.

Aqueous humor is predominantly secreted to the posterior chamber of theeye by the ciliary processes of the ciliary body and a minor mechanismof aqueous humor production is through ultrafiltration from arterialblood (FIG. 1). Aqueous humor then reaches the anterior chamber bycrossing the pupil and there are convection currents where the flow ofaqueous adjacent to the iris is upwards, and the flow of aqueousadjacent to the cornea flows downwards (FIG. 2).

There are two different pathways of aqueous humor outflow, both locatedin the iridocorneal angle of the eye (FIG. 1). The uveoscleral ornonconventional pathway refers to the aqueous humor leaving the anteriorchamber by diffusion through intercellular spaces among ciliary musclefibers. Although this seems to be a minority outflow pathway in humans,the uveoscleral or nonconventional pathway is the target of specificanti-hypertensive drugs such as the hypotensive lipids that increase thefunctionality of this route through remodeling of the extracellularmatrix.

The aqueous humor drains 360 degrees into the trabecular meshwork thatinitially has pore size diameters ranging from 10 to under 30 microns inhumans. Aqueous humor drains through Schlemm's canal and exits the eyethrough 25 to 30 collector channels into the aqueous veins, andeventually into the episcleral vasculature and veins of the orbit (seeFIG. 3). FIG. 3 is a schematic drawing in which the arrows indicateaqueous humor convection currents in the anterior chamber of an eye. Animplant as described herein releasing at least one therapeutic agent isshown placed inferiorly. Free therapeutic agents eluting from theimplant enters the aqueous humor convection currents (arrows). Thetherapeutic agents are then dispersed throughout the anterior chamberand enter the target tissues such as the trabecular meshwork and theciliary body region through the iris root region.

An advantage of intracameral injection and placement of thebiodegradable implant described herein is that the anterior chamber isan immune privileged site in the body and less likely to react toforeign material, such as polymeric therapeutic agent delivery systems.This is not the case in the sub-Tenon's space where inflammatoryreactions to foreign materials are common. In addition to the anteriorchamber containing immunoregulatory factors that confer immuneprivilege, particles with diameters greater than 30 microns are lessimmunogenic and have a lower propensity toward causing ocularinflammation. Resident macrophages in the eye are the first line ofdefense with foreign bodies or infectious agents; however, particleslarger than 30 microns are difficult to phagocytose. Therefore,particles larger than 30 microns are less prone to macrophage activationand the inflammatory cascade that follows. This reduction ininflammation response is beneficial to a patient.

The efficiency of delivering therapeutic agents or drugs to the aqueoushumor with a polymeric release system is much greater with anintracameral location when compared to a sub-Tenon application. Thus,less than 1% of therapeutic agent delivered in the sub-Tenon's spacewill enter the aqueous humor whereas 100% of the drug releasedintracamerally will enter the aqueous humor. Therefore, lowertherapeutic agent loads are required for the intracameral drug deliverysystems described herein compared to sub-Tenon's applications.

As such, there will be less exposure of the conjunctiva to therapeuticagents, and as a result, less propensity toward developing conjunctivalhyperemia when delivering topical therapeutic agents, such asprostaglandins and prostamines. Lastly, the therapeutic agent(s) willenter the conjunctival/episcleral blood vessel via the aqueous veinsdirectly following intracameral implantation. This minimizesconjunctival hyperemia with, for example, prostaglandin analoguescompared with a sub-Tenon's injection where numerous vessels are at riskof dilation with a high concentration of therapeutic agent presentdiffusely in the extravascular space of the conjunctiva. Directintracameral implantation also obviates the need for preservatives,which when used in topical drops, can irritate the ocular surface.

The implants described herein are made of polymeric materials to providemaximal approximation of the implant to the iridocorneal angle. Inaddition, the size of the implant, which ranges from a diameter, widthor cross-section of about 0.1 mm to about 1 mm, and lengths from about0.1 mm to about 6 mm, enables the implant to be inserted into theanterior chamber using an applicator with a small gauge needle rangingfrom about 22 G to about 30 G.

The polymer materials used to form the implants described herein can beany combination of polylactic acid, glycolic acid, and/or polyethyleneglycol that provides sustained-release of the therapeutic agent into theoutflow system of the eye over time. Other polymer-based sustainedrelease therapeutic agent delivery systems for hypotensive lipids canalso be used intracamerally to reduce IOP.

The intracameral implants described herein can release therapeutic agentloads over various time periods. The implants, when insertedintracamerally or into the anterior vitreous, provide therapeutic levelsof at least one therapeutic agent for extended periods of time. Extendedperiods of time can be about 1 week, about 6 weeks, about 6 months,about 1 year or longer.

Suitable polymeric materials or compositions for use in the implantsinclude those materials which are compatible, that is biocompatible,with the eye so as to cause no substantial interference with thefunctioning or physiology of the eye. Such materials preferably are atleast partially, and more preferably, substantially biodegradable orbioerodible.

In one embodiment, examples of useful polymeric materials include,without limitation, such materials derived from and/or including organicesters and organic ethers, which when degraded result in physiologicallyacceptable degradation products, including the monomers. Also, polymericmaterials derived from and/or including, anhydrides, amides, orthoestersand the like, by themselves or in combination with other monomers, mayalso find use. The polymeric materials may be addition or condensationpolymers, advantageously condensation polymers. The polymeric materialsmay be cross-linked or non-cross-linked, for example not more thanlightly cross-linked, such as less than about 5%, or less than about 1%of the polymeric material being cross-linked. For the most part, besidescarbon and hydrogen, the polymers will include at least one of oxygenand nitrogen, advantageously oxygen. The oxygen may be present as oxy,e.g. hydroxy or ether, carbonyl, e.g. non-oxo-carbonyl, such ascarboxylic acid ester, and the like. The nitrogen may be present asamide, cyano and amino.

In one embodiment, polymers of hydroxyaliphatic carboxylic acids, eitherhomopolymers or copolymers, and polysaccharides are useful in theimplants. Polyesters can include polymers of D-lactic acid, L-lacticacid, racemic lactic acid, glycolic acid, polycaprolactone, andcombinations thereof. Generally, by employing the L-lactate orD-lactate, a slowly eroding polymer or polymeric material is achieved,while erosion is substantially enhanced with the lactate racemate.Useful polysaccharides and polyethers can include, without limitation,polyethylene glycol (PEG), calcium alginate, and functionalizedcelluloses, particularly carboxymethylcellulose esters characterized bybeing water insoluble and having a molecular weight of about 5 kD toabout 500 kD, for example.

Other polymers of interest include, without limitation, polyvinylalcohol, polyesters, and combinations thereof which are biocompatibleand may be biodegradable and/or bioerodible. Some preferredcharacteristics of the polymers or polymeric materials for use in thepresent implants may include biocompatibility, compatibility with theselected therapeutic agent, ease of use of the polymer in making thetherapeutic agent delivery systems described herein, a desired half-lifein the physiological environment, and water insolubility.

In one embodiment, an intracameral implant according to the presentdescription has a formulation of 30% therapeutic agent, 45% R203Spoly(D,L-lactide), 20% R202H poly(D,L-lactide), and 5% PEG 3350. Inanother embodiment, the formulation is 20% therapeutic agent, 45% R203Spoly(D,L-lactide), 10% R202H poly(D,L-lactide), 20% RG752Spoly(DL-lactide-co-glycolide), and 5% PEG 3350. The range ofconcentrations of the constituents that can be used are about 5% toabout 40% therapeutic agent, about 10% to about 60% R203S, about 5% toabout 20% R202H, about 5% to about 40% RG752S, and 0 to about 15% PEG3350. Specific polymers may be omitted, and other types added, to adjustthe therapeutic agent release rates. The polymers used are commerciallyavailable.

The polymers used to form the implant have independent propertiesassociated with them that when combined provide the properties neededfor sustained release of at least one therapeutic agent once implanted.For example, R203S poly(D,L-lactide) has an inherent viscosity, or meanviscosity, of about 0.25 to about 0.35 dl/g whereas R202Hpoly(D,L-lactide) has a lower inherent viscosity of about 0.16 to about0.24 dl/g. As such, the polymer compositions described herein can have amixture of higher and lower molecular weight poly(D,L-lactide).Likewise, RG752S poly(DL-lactide-co-glycolide) has a molar ratio ofD,L-lactide:glycolide of about 73:27 to about 77:23 and an inherentviscosity of about 0.16 to about 0.24 dl/g. The polyethylene glycol usedherein can have a molecular weight for example of about 3,000 to about3,500 g/mol, preferably about 3,350 g/mol. Polymers having differentinherent viscosities and/or molecular weights can be combined to arriveat a polymeric composition appropriate for sustained release of aparticular therapeutic agent or agents.

The biodegradable polymeric materials which are included to form theimplant's polymeric matrix are preferably subject to enzymatic orhydrolytic instability. Water soluble polymers may be cross-linked withhydrolytic or biodegradable unstable cross-links to provide useful waterinsoluble polymers. The degree of stability can be varied widely,depending upon the choice of monomer, whether a homopolymer or copolymeris employed, employing mixtures of polymers, and whether the polymerincludes terminal acid groups.

Equally important to controlling the biodegradation of the polymer andhence the extended release profile of the implant is the relativeaverage molecular weight of the polymeric composition employed in theimplants. Different molecular weights of the same or different polymericcompositions may be included to modulate the release profile of the atleast one therapeutic agent.

The implants described herein can be monolithic, i.e. having the atleast one therapeutic agent homogenously distributed throughout thepolymeric matrix, or encapsulated, where a reservoir of therapeuticagent is encapsulated by the polymeric matrix. In addition, thetherapeutic agent may be distributed in a non-homogenous pattern in thematrix. For example, the implants may include a portion that has agreater concentration of the therapeutic agent relative to a secondportion of the implant which may have less.

The total weight of an implant is dependent on the volume of theanterior chamber and the activity or solubility of the therapeuticagent. Often, the dose of therapeutic agent is generally about 0.1 mg toabout 200 mg of implant per dose. For example, an implant may weighabout 1 mg, about 3 mg, about 5 mg, about 8 mg, about 10 mg, about 100mg about 150 mg, about 175 mg, or about 200 mg, including theincorporated therapeutic agent.

A load of therapeutic agent associated with an implant will have asustained release property or profile associated with it. For example,over the first 30 days after implantation, the implants described hereincan release about 1 μg/day to about 20 μg/day. Over the lifetime of animplant, about 100 ng/day to about 900 ng/day can be released. In otherembodiments, about 300 ng/day, about 675 ng/day or about 700 ng/day oftherapeutic agent is released.

The proportions of the therapeutic agent, polymer and any othermodifiers may be empirically determined by formulating several implantbatches with varying average proportions. Release rates can be estimate,for example, using the infinite sink method, a weighed sample of theimplants is added to a measured volume of a solution containing 0.9%NaCl in water, where the solution volume will be such that thetherapeutic agent concentration after release is less than 5% ofsaturation. The mixture is maintained at 37° C. and stirred slowly. Theappearance of the dissolved therapeutic agent as a function of time maybe followed by various methods known in the art, such asspectrophotometrically, HPLC, mass spectroscopy, and the like until theabsorbance becomes constant or until greater than 90% of the therapeuticagent has been released.

The therapeutic agents that can be used with the implants describedherein are prostaglandins, prostaglandin analogues, and prostamides.Examples include prostaglandin receptor agonists including prostaglandinE₁ (alprostadil), prostaglandin E₂ (dinoprostone), latanoprost andtravoprost. Latanoprost and travoprost are prostaglandin prodrugs (i.e.I-isopropyl esters of a prostaglandin); however, they are referred to asprostaglandins because they act on the prostaglandin F receptor, afterbeing hydrolyzed to the 1-carboxylic acid. A prostamide (also called aprostaglandin-ethanolamide) is a prostaglandin analogue, which ispharmacologically unique from a prostaglandin (i.e. because prostamidesact on a different cell receptor [the prostamide receptor] than doprostaglandins), and is a neutral lipid formed a as product ofcyclo-oxygenase-2 (“COX-2”) enzyme oxygenation of an endocannabinoid(such as anandamide). Additionally, prostamides do not hydrolyze in situto the 1-carboxylic acid. Examples of prostamides are bimatoprost (thesynthetically made ethyl amide of 17-phenyl prostaglandin F_(2α)) andprostamide F_(2α). Other prostaglandin analogues that can be used astherapeutic agents include, but are not limited to, unoprostone, andEP₂/EP₄ receptor agonists.

Prostaglandins as used herein also include one or more types ofprostaglandin derivatives, prostaglandin analogues including prostamidesand prostamide derivatives, prodrugs, salts thereof, and mixturesthereof. In certain implants, the prostaglandin comprises a compoundhaving the structure

wherein the dashed bonds represent a single or double bond which can bein the cis or trans configuration; A is an alkylene or alkenyleneradical having from two to six carbon atoms, which radical may beinterrupted by one or more oxide radicals and substituted with one ormore hydroxy, oxo, alkyloxy or akylcarboxy groups wherein the alkylradical comprises from one to six carbon atoms; B is a cycloalkylradical having from three to seven carbon atoms, or an aryl radical,selected from hydrocarbyl aryl and heteroaryl radicals having from fourto ten carbon atoms wherein the heteroatom is selected from nitrogen,oxygen and sulfur atoms; X is-OR⁴ or —N(R⁴)₂ wherein R⁴ is selected fromhydrogen, a lower alkyl radical having from one to six carbon atoms,

wherein R⁵ is a lower alkyl radical having from one to six carbon atoms;Z is =0 or represents two hydrogen radicals; one of R¹ and R² is =0, —OHor a —O(CO)R⁶ group, and the other one is —OH or —O(CO)R⁶, or R¹ is =0and R² is hydrogen, wherein R⁶ is a saturated or unsaturated acyclichydrocarbon group having from 1 to about 20 carbon atoms, or—(CH₂)_(m)R⁷ wherein m is 0 or an integer of from 1 to 10, and R⁷ iscycloalkyl radical, having from three to seven carbon atoms, or ahydrocarbyl aryl or heteroaryl radical, as defined above, or apharmaceutically-acceptable salt thereof.

Pharmaceutically acceptable acid addition salts of the compoundsdescribed are those formed from acids which form non-toxic additionsalts containing pharmaceutically acceptable anions, such as thehydrochloride, hydrobromide, hydroiodide, sulfate, or bisulfate,phosphate or acid phosphate, acetate, maleate, fumarate, oxalate,lactate, tartrate, citrate, gluconate, saccharate and p-toluenesulphonate salts.

In one example embodiment, the implants include a prostaglandin havingthe structure

wherein y is 0 or 1, x is 0 or 1 and x and y are not both 1, Y isselected the group consisting of alkyl, halo, nitro, amino, thiol,hydroxy, alkyloxy, alkylcarboxy and halo substituted alkyl, wherein saidalkyl radical comprises from one to six carbon atoms, n is 0 or aninteger of from 1 to 3 and R³ is =0, —OH or O(CO)R⁶.

In additional example embodiments, the prostaglandin has the formula

wherein hatched lines indicate the alpha configuration and solidtriangles indicate the beta configuration.

In some implants described herein, the prostaglandin has the formula

wherein Y¹ is Cl or trifluoromethyl.

Other prostaglandins can have the following formula

and 9-, 11- and/or 15 esters thereof.

In one example embodiment, the prostaglandin component comprises acompound having the formula

This compound is also known as bimatoprost and is publicly available ina topical ophthalmic solution under the tradename, LUMIGAN® (Allergan,Inc., Irvine, Calif.).

In another example embodiment of an intraocular implant, theprostaglandin comprises a compound having the structure

This prostaglandin is known as latanoprost and is publicly available ina topical ophthalmic solution under the tradename, XALATAN®. Thus, theimplants may comprise at least one therapeutic bioactive agent whichcomprises, consists essentially of, or consists of latanoprost, a saltthereof, isomer, prodrug or mixtures thereof.

The prostaglandin component may be in a particulate or powder form andit may be entrapped by the biodegradable polymer matrix. Usually,prostaglandin particles will have an effective average size less thanabout 3000 nanometers. In certain implants, the particles may have aneffective average particle size about an order of magnitude smaller than3000 nanometers. For example, the particles may have an effectiveaverage particle size of less than about 500 nanometers. In additionalimplants, the particles may have an effective average particle size ofless than about 400 nanometers, and in still further embodiments, a sizeless than about 200 nanometers.

Other therapeutic agents useful with the intracameral implants describedherein, include, but are not limited to beta-adrenergic receptorantagonists (such as timolol, betaxolol, levobetaxolol, carteolol,levobunolol, and propranolol, which decrease aqueous humor production bythe ciliary body); alpha adrenergic receptor agonists such asbrimonidine and apraclonidine (iopidine) (which act by a dual mechanism,decreasing aqueous production and increasing uveoscleral oufflow);less-selective sympathomimetics such as epinephrine and dipivefrin (actto increase oufflow of aqueous humor through trabecular meshwork andpossibly through uveoscleral oufflow pathway, probably by a beta2-agonist action); carbonic anhydrase inhibitors such as dorzolamide,brinzolamide, acetazolamide (lower secretion of aqueous humor byinhibiting carbonic anhydrase in the ciliary body); rho-kinaseinhibitors (lower IOP by disrupting the actin cytoskeleton of thetrabecular meshwork; vaptans (vasopressin-receptor antagonists);anecortave acetate and analogues; ethacrynic acid; cannabinoids;cholinergic agonists including direct acting cholinergic agonists(miotic agents, parasympathomimetics) such as carbachol, pilocarpinehydrochloride; pilocarbine nitrate, and pilocarpine (acts by contractionof the ciliary muscle, tightening the trabecular meshwork and allowingincreased outflow of the aqueous humor); chlolinesterase inhibitors suchas demecarium, echothiophate and physostigmine; glutamate antagonists;calcium channel blockers including memantine, amantadine, rimantadine,nitroglycerin, dextrophan, detromethorphan, dihydropyridines, verapamil,emopamil, benzothiazepines, bepridil, diphenylbutylpiperidines,diphenylpiperazines, fluspirilene, eliprodil, ifenprodil, tibalosine,flunarizine, nicardipine, nifedimpine, nimodipine, barnidipine,verapamil, lidoflazine, prenylamine lactate and amiloride; prostamidessuch as bimatoprost, or pharmaceutically acceptable salts or prodrugsthereof; and prostaglandins including travoprost, chloprostenol,fluprostenol, 13,14-dihydro-chloprostenol, isopropyl unoprostone, andlatanoprost; AR-I 02 (a prostaglandin FP agonist available from AeriePharmaceuticals, Inc.); AL-3789 (anecortave acetate, an angiostaticsteroid available from Alcon); AL-6221 (travaprost rravatan] aprostaglandin FP agonist; PF-03187207 (a nitric oxide donatingprostaglandin available from by Pfizer) PF-04217329 (also available fromPfizer); INS1 15644 (a lantrunculin B compound available from InspirePharmaceuticals), and; INS1 17548 (Rho-kinase inhibitor also availablefrom inspire Pharmaceuticals).

Combinations of ocular anti-hypertensives, such as a beta blocker and aprostaglandin/prostamide analogue, can also be used in the deliverysystems described herein. These include bimatoprostltimolol,travoprostltimolol, latanoprostltimolol, brimonidine/timolol, anddorzolamide/timolol. In combination with an IOP lowering therapeuticagent, an agent that confers neuroprotection can also be placed in thedelivery system and includes memantine and serotonergics [e.g.,5-HT.sub.2 agonists, such as but not limited to, S-(+)-I-(2-aminopropyl)-indazole-6-01)].

Other therapeutic agents outside of the class of ocular hypotensiveagents can be used with the intracameral implants to treat a variety ofocular conditions. For example, anti-VEGF and other anti-angiogenesiscompounds can be used to treat neovascular glaucoma. Another example isthe use of corticosteroids or calcineurin inhibitors that can be used totreat diseases such as uveitis and corneal transplant rejection. Theseimplants can also be placed in the subconjunctival space and in thevitreous.

Additionally, described herein are novel methods for making implants.The therapeutic agent of the present implants is preferably from about1% to about 90% by weight of the implant. More preferably, thetherapeutic agent is from about 5% to about 30% by weight of theimplant. In a preferred embodiment, the therapeutic agent is ananti-hypertensive agent and comprises about 15% by weight of the implant(e.g., 5%-30 weight %). In another embodiment, the anti-hypertensiveagent comprises about 20% or about 30% by weight of the implant.

In addition to the therapeutic agent, the implants described herein caninclude or may be provided in compositions that include effectiveamounts of buffering agents, preservatives and the like. Suitable watersoluble buffering agents include, without limitation, alkali andalkaline earth carbonates, phosphates, bicarbonates, citrates, borates,acetates, succinates and the like, such as sodium phosphate, citrate,borate, acetate, bicarbonate, carbonate and the like. These agents canbe present in amounts sufficient to maintain a pH of the system ofbetween about 2 to about 9 and more preferably about 4 to about 8. Assuch the buffering agent may be as much as about 5% by weight of thetotal implant. Suitable water soluble preservatives include sodiumbisulfite, sodium bisulfate, sodium thiosulfate, ascorbate, benzalkoniumchloride, chlorobutanol, thimerosal, phenylmercuric acetate,phenylmercuric borate, phenylmercuric nitrate, parabens, methylparaben,polyvinyl alcohol, benzyl alcohol, phenylethanol and the like andmixtures thereof. These agents may be present in amounts of from about0.001% to about 5% by weight and preferably about 0.01% to about 2% byweight of the implant.

In one embodiment, a preservative such as benzylalkonium chloride isprovided in the implant. In another embodiment, the implant can includeboth benzylalkonium chloride and bimatoprost. In yet another embodiment,the bimatoprost is replaced with latanoprost.

Various techniques may be employed to produce the implants describedherein. Useful techniques include, but are not necessarily limited to,self-emulsification methods, super critical fluid methods, solventevaporation methods, phase separation methods, spray drying methods,grinding methods, interfacial methods, molding methods, injectionmolding methods, combinations thereof and the like.

In one embodiment, the methods for making the implants involvedissolving the appropriate polymers and therapeutic agents in a solvent.Solvent selection will depend on the polymers and therapeutic agentschosen. For the implants described herein, including a therapeutic agentsuch as latanoprost, dichloromethane (DCM) is an appropriate solvent.Once the polymers and therapeutic agent(s) have been dissolved, theresulting mixture is cast into a die of an appropriate shape.

Then, once cast, the solvent used to dissolve the polymers andtherapeutic agent(s) is evaporated at a temperature between about 20° C.and about 30° C., preferably about 25° C. The polymer can be dried atroom temperature or even in a vacuum. For example, the cast polymersincluding therapeutic agents can be dried by evaporation in a vacuum.

The dissolving and casting steps form the implants because dissolvingthe polymers and therapeutic agents allows the system to naturallypartition and form into its most natural configuration based onproperties such as polymer viscosity and hence molecular weight, polymerhydrophobicity/hydophilicty, therapeutic agent molecular weight,therapeutic agent hydrophobicity/hydophilicty and the like.

Once the cast polymers are dried, they can be processed into an implantusing any method known in the art to do so. In an example embodiment,the dried casted polymer can be cut into small pieces and extruded intorounded or squared rod shaped structures at a temperature between about50° C. and about 120° C., preferably about 90° C. In other exampleembodiments, the films can simply be cast without extrusion.

Other methods involve extrusion of dry polymer powders and dry or liquidtherapeutic agents. The implants are extruded and formed into a randomorientation depending on the dry powder mix itself and not based onphysical properties of the components. Prostaglandins such aslatanoprost are very difficult to incorporate into hot-melt extrudedimplants because they generally exude the prostaglandin when heated.Therefore, the extrusion temperature is kept as low as possible to avoidloss and degradation of the prostaglandin. This can be accomplished byusing a select combination of appropriate molecular weight polymers anda plasticizer like (polyethyleneglycol) PEG that are compatible with theprostaglandin. The prostaglandin and PEG plasticize the polymers to adegree that allows the mixture to be extruded at a temperature where theprostaglandin is not degraded or lost.

The therapeutic agent containing implants disclosed herein can be usedto treat other ocular conditions in addition to glaucoma and/orincreased IOP, such as the following: maculopathies/retinaldegeneration: macular degeneration, including age related maculardegeneration (ARMD), such as non-exudative age related maculardegeneration and exudative age related macular degeneration, choroidalneovascularization, retinopathy, including diabetic retinopathy, acuteand chronic macular neuroretinopathy, central serous chorioretinopathy,and macular edema, including cystoid macular edema, and diabetic macularedema. Uveitis/retinitis/choroiditis: acute multifocal placoid pigmentepitheliopathy, Behcet's disease, birdshot retinochoroidopathy,infectious (syphilis, lyme, tuberculosis, toxoplasmosis), uveitis,including intermediate uveitis (pars planitis) and anterior uveitis,multifocal choroiditis, multiple evanescent white dot syndrome (MEWDS),ocular sarcoidosis, posterior scleritis, serpignous choroiditis,subretinal fibrosis, uveitis syndrome, and Vogt-Koyanagi-Haradasyndrome. Vascular diseases/exudative diseases: retinal arterialocclusive disease, central retinal vein occlusion, disseminatedintravascular coagulopathy, branch retinal vein occlusion, hypertensivefundus changes, ocular ischemic syndrome, retinal arterialmicroaneurysms, Coat's disease, parafoveal telangiectasis, hemi-retinalvein occlusion, papillophlebitis, central retinal artery occlusion,branch retinal artery occlusion, carotid artery disease (CAD), frostedbranch angitis, sickle cell retinopathy and other hemoglobinopathies,angioid streaks, familial exudative vitreoretinopathy, Eales disease.Traumatic/surgical: sympathetic ophthalmia, uveitic retinal disease,retinal detachment, trauma, laser, PDT, photocoagulation, hypoperfusionduring surgery, radiation retinopathy, bone marrow transplantretinopathy. Proliferative disorders: proliferative vitreal retinopathyand epiretinal membranes, proliferative diabetic retinopathy. Infectiousdisorders: ocular histoplasmosis, ocular toxocariasis, presumed ocularhistoplasmosis syndrome (PONS), endophthalmitis, toxoplasmosis, retinaldiseases associated with HIV infection, choroidal disease associatedwith HIV infection, uveitic disease associated with HIV Infection, viralretinitis, acute retinal necrosis, progressive outer retinal necrosis,fungal retinal diseases, ocular syphilis, ocular tuberculosis, diffuseunilateral subacute neuroretinitis, and myiasis. Genetic disorders:retinitis pigmentosa, systemic disorders with associated retinaldystrophies, congenital stationary night blindness, cone dystrophies,Stargardt's disease and fundus flavimaculatus, Bests disease, patterndystrophy of the retinal pigmented epithelium, X-linked retinoschisis,Sorsby's fundus dystrophy, benign concentric maculopathy, Bietti'scrystalline dystrophy, pseudoxanthoma elasticum. Retinal tears/holes:retinal detachment, macular hole, giant retinal tear. Tumors: retinaldisease associated with tumors, congenital hypertrophy of the RPE,posterior uveal melanoma, choroidal hemangioma, choroidal osteoma,choroidal metastasis, combined hamartoma of the retina and retinalpigmented epithelium, retinoblastoma, vasoproliferative tumors of theocular fundus, retinal astrocytoma, intraocular lymphoid tumors.Miscellaneous: punctate inner choroidopathy, acute posterior multifocalplacoid pigment epitheliopathy, myopic retinal degeneration, acuteretinal pigment epithelitis and the like.

In one example embodiment, an implant comprising both PLA, PEG and PLGAand including an anti-hypertensive agent is used because implants ofsuch a composition result in significantly less inflammatory (e.g. lesscorneal hyperemia) upon intracameral or anterior vitreal administration.Another embodiment can comprise a therapeutic agent delivery system witha plurality of anti-hypertensive agents contained in different segmentsof the same implant. For example, one segment of an implant can containa muscarinic anti-hypertensive agent, a second segment of the implantcan contain a anti-hypertensive prostaglandin and third segment of theimplant can contain an anti-hypertensive beta blocker. Such an implantcan be injected to enhance aqueous outflow through the trabecularmeshwork, to enhance uveoscleral flow and to reduce aqueous humorproduction. Multiple hypotensive agents with different mechanisms ofaction can be more effective at lowering IOP than monotherapy, that isuse of a single type of an anti-hypertensive agent. A multiple segmentedimplant has the advantage of permitting lower doses of each separatetherapeutic agent used than the dose necessary with monotherapy, therebyreducing the side effects of each therpaeutic agent used.

In one embodiment, when using a multiple segmented implant, each segmentis preferably has a length no greater than about 2 mm. Preferably, thetotal umber of segments administered through a 22 G to 25 G diameterneedle bore is about four. With a 27 G diameter needle total segmentslength within the needle bore or lumen can be up to about 12 mm.

The fluid uptake action of the TM can be exploited to keep implants thathave an appropriate geometry from floating around the anterior chambercausing visual obscuration. Gravity brings these implants down to aboutthe 6 o'clock position, for example from about 20 degrees plus or minus,and the implants are stable (immobile) in this position. Implants thatcan be intraocularly administered by a 22 G to 30 G diameter needle withlengths totaling no more than about 6 to 8 mm are most preferred to takeadvantage of the TM fluid uptake mechanism with resulting intraocularimplant immobility and no visual obscuration. Thus, despite being firmlyin the 6 o'clock position in the anterior chamber due to TM fluid uptakeeffect, the implants can have release rates that exceed the TM clearancerate and this allows therapeutic agent(s) released by the implants torapidly fill the anterior chamber and distribute well into the targettissues along a 360 degrees distribution pattern. Examination ofimplants in the angle of the anterior chamber with gonioscopy have shownthat the there is no encapsulation of nor inflammatory tissue in thevicinity of the implants.

Delivery of therapeutic agents to the front of the eye (anteriorchamber) can both lower intraocular pressure (IOP) and evade aggressiveclearance of the transscleral barriers. Intracameral injections (i.e.direct injection into the anterior chamber) of implants as describedherein and anterior vitreous injections of the same through the parsplana effectively avoid the transscleral barriers and improve theefficacy of the ocular anti-hypertensive compounds. Importantly, thepresent implants required development of new sustained releasedtherapeutic agent delivery systems with particular physical features andrequired therapeutic efficacy because of the unique anatomy andphysiology of the anterior chamber.

In one example embodiment, bimatoprost can be used in the implantsdescribed herein. Bimatoprost may improve aqueous outflow through thetrabecular meshwork (TM) mediated through a prostamide receptor. In thehuman eye, the main outflow route is the trabecular or conventionaloutflow pathway. This tissue contains three differentiated layers. Fromthe inner to the outermost part, the layer of tissue closest to theanterior chamber is the uveal meshwork, formed by prolongations ofconnective tissue arising from the iris and ciliary body stromas andcovered by endothelial cells. This layer does not offer much resistanceto aqueous humor outflow because intercellular spaces are large. Thenext layer, known as the corneoscleral meshwork, is characterized by thepresence of lamellae covered by endothelium-like cells on a basalmembrane. The lamellae are formed by glycoproteins, collagen, hyaluronicacid, and elastic fibers. The higher organization of the corneoscleralmeshwork, in relation to the uveal meshwork, as well as their narrowerintercellular spaces, are responsible for the increase in flowresistance. The third layer, which is in direct contact with the innerwall of endothelial cells from Schlemm's canal, is the juxtacanalicularmeshwork. It is formed by cells embedded in a dense extracellularmatrix, and the majority of the tissue resistance to aqueous flow ispostulated to be in this layer, due to its narrow intercellular spaces.The layer of endothelial cells from Schlemm's canal has expandable poresthat transfer the aqueous into the canal and accounts for approximately10% of the total resistance. It is thought that aqueous humor crossesthe inner wall endothelium of Schlemm's canal by two differentmechanisms: a paracellular route through the junctions formed betweenthe endothelial cells and a transcellular pathway through intracellularexpandable pores of the same cells. Once there is entry into Schlemm'scanal (FIG. 2), the aqueous drains directly into the collector ducts andaqueous veins that anastomose with the episcleral and conjunctival plexiof vessels. Aqueous humor outflow via the trabecular pathway is IOPdependent, usually measured as outflow facility, and expressed inmicroliters per minute per millimeter of mercury.

The episcleral venous pressure controls outflow through the collectorchannels and is one factor that contributes to the intraocular pressure.Increases in the episcleral venous pressure such as seen withcarotid-cavernous sinus fistulas, orbital varices, and Sturge-WeberSyndrome, can lead to difficult to manage glaucoma. Reducing episcleralvenous pressure in disease states, such as treating carotid-cavernoussinus fistulas, can normalize the episcleral venous pressure and reducethe intraocular pressure. Targeting the outflow channels and vessels toreduce the episcleral venous pressure with pharmacotherapy may reducethe IOP.

Example 1

A series of three experiments were performed comparing the fluctuationsof IOP over time in groups of animals treated with either bimatoprosteye drops or an intracameral sustained release bimatoprost implant asdescribed herein. IOPs were recorded over time and the mean of the IOPsfor each animal was calculated after dosing. The standard deviation (SD)of the mean was used to compare the variability of IOP control for eachanimal, and the average of all the SD means was calculated. A lowernumber for example, would correspond to less IOP fluctuation. This finalSD value was calculated for all animals in the topical dosed group andalso calculated for all animals receiving an intracameral implant, andthe values were compared to determine if the intracameral implants weremore effective at reducing IOP fluctuation.

Experiment 1:

Six normal beagle dogs had one drop bimatoprost 0.03% ophthalmicsolution (LUMIGAN®) instilled in the left eye daily. Recordings of IOPwere made with a pneumatonometer at about 10 am. Table 1 displays IOPrecordings in mmHG at weekly intervals for 1 month in 6 dogs takingdaily bimatoprost eye drops. The average of the mean of the SD for eachanimal is 1.38 mm Hg.

TABLE 1 Bimatoprost 0.03% Ophthalmic Drops: IOP Results Dog A Dog B DogC Dog D Dog E Dog F Baseline 15.7 20.2 16.5 20.7 12.7 20.7 IOP (mmHG)Day 8 8.3 8.0 9.7 10.0 10.0 7.5 Day 15 7.2 6.2 8.8 9.0 6.8 10.3 Day 228.5 7.8 12.8 9.2 7.5 14.5 Day 29 9.0 7.7 11.7 9.3 9.5 11.3 Mean 8.3 7.410.8 9.4 8.5 10.9 SD 0.76 0.83 1.83 0.43 1.54 2.89

Experiment 2:

A bimatoprost implant with a formulation containing 30% therapeuticagent, 45% R2035, 20% R202H and 5% PEG 3350 was manufactured with atotal implant weight of 900 ug (drug load 270 ug). The in vitro releaserates of this implant are graphically illustrated in FIG. 4. Thisimplant released about 70% over first 30 days. An implant with a 270 ugdrug load would release 189 ug over first 30 days or 6.3 ug per day. Theremainder of the implant (81 ug) is released over the next four months(e.g. 675 ng per day).

Normal beagle dogs were given general anesthesia and a 3 mm widekeratome blade was used to enter the anterior chamber of the right eyes.A bimatoprost implant was placed in the anterior chamber and it settledout in the inferior angle within 24 hours. The IOP results are shown inTable 2. The average of the mean of the SD for each animal is 0.57 mm Hgwith Dog #4 having a first month mean SD of 0.

TABLE 2 Intracameral Bimatoprost Implant: IOP Results Dog #1 Dog #2 Dog#3 Dog #4 120 ug 120 ug 120 ug 270 ug Baseline IOP 17.0 16.5 22.5 25.0(mmHG) Day 7 11.5 9.0 14.0 9.0 Day 14 10.5 9.0 14.5 n/a Day 21 11.5 11.013.5 n/a Day 28 11.0 11.0 13.0 9.0 Mean 11.1 10.0 13.8 9.0 SD 0.48 1.150.65 0

Experiment 3:

An additional bimatoprost implant formulation with 20% therapeuticagent, 45% R203S, 10% R202H, 20% RG752S and 5% PEG 3350 formulation wasmanufactured with a total implant weight of about 300 ug (drug load ofabout 60 ug). Implant weights are shown in Table 3, each animal receivedtwo implants. The in vitro release rates of this implant are shown inFIG. 5. Table 3 shows implant weights and therapeutic agent loads usedin the dogs for Experiment 3. Each animal received 2 intracameralimplants to 1 eye. The implants release about 15% of the drug load overthe first month. An implant with a 60 ug drug load would release 9 ugover the first 30 days or 300 ng per day, thereafter. In other words,the implant releases about 50 ug over 60 days or about 700 ng/day.

TABLE 3 Implant weights Implant Weight Total Therapeutic Agent Dog ID(mg) Dose (20% load, ug) Dog #1 0.302 126.6 0.331 Dog #2 0.298 125.40.329 Dog #3 0.0306 126.6 0.327

Implants were loaded in customized applicators with a 25 G UTW needles.Under general anesthesia, normal beagle dogs had the implant inserted inthe right anterior chamber through clear cornea and the wound wasself-sealing. Each animal (n=3) received two implants in the right eye.The implant demonstrated no inflammation clinically and a representativephotograph of an implant in the anterior chamber is seen in FIG. 6. TheIOP results and the SD of the mean over the first month are shown inTable 2. The average of the mean of the SD's in Table 2 of the four dogs(total) from experiments 2 and 3 treated with bimatoprost implants was0.57 mmHg.

The variability in the IOP of the dogs in Experiment 1 dosed withbimatoprost eye drops as measured by the final SD value was 1.38 mmHg.In contrast, the final SD value with sustained-release bimatoprostimplants was 0.57 mmHg. There was approximately a three-fold reductionin the final SD value demonstrating that sustained-release bimatoprostimplant described herein is superior to bolus dosing with topicalbimatoprost to reduce IOP fluctuations over time.

Unless otherwise indicated, all numbers expressing quantities ofingredients, properties such as molecular weight, reaction conditions,and so forth used in the specification and claims are to be understoodas being modified in all instances by the term “about.” Accordingly,unless indicated to the contrary, the numerical parameters set forth inthe specification and attached claims are approximations that may varydepending upon the desired properties sought to be obtained by thepresent invention. At the very least, and not as an attempt to limit theapplication of the doctrine of equivalents to the scope of the claims,each numerical parameter should at least be construed in light of thenumber of reported significant digits and by applying ordinary roundingtechniques. Notwithstanding that the numerical ranges and parameterssetting forth the broad scope of the invention are approximations, thenumerical values set forth in the specific examples are reported asprecisely as possible. Any numerical value, however, inherently containscertain errors necessarily resulting from the standard deviation foundin their respective testing measurements.

The terms “a,” “an,” “the” and similar referents used in the context ofdescribing the invention (especially in the context of the followingclaims) are to be construed to cover both the singular and the plural,unless otherwise indicated herein or clearly contradicted by context.Recitation of ranges of values herein is merely intended to serve as ashorthand method of referring individually to each separate valuefalling within the range. Unless otherwise indicated herein, eachindividual value is incorporated into the specification as if it wereindividually recited herein. All methods described herein can beperformed in any suitable order unless otherwise indicated herein orotherwise clearly contradicted by context. The use of any and allexamples, or exemplary language (e.g., “such as”) provided herein isintended merely to better illuminate the invention and does not pose alimitation on the scope of the invention otherwise claimed. No languagein the specification should be construed as indicating any non-claimedelement essential to the practice of the invention.

Groupings of alternative elements or embodiments of the inventiondisclosed herein are not to be construed as limitations. Each groupmember may be referred to and claimed individually or in any combinationwith other members of the group or other elements found herein. It isanticipated that one or more members of a group may be included in, ordeleted from, a group for reasons of convenience and/or patentability.When any such inclusion or deletion occurs, the specification is deemedto contain the group as modified thus fulfilling the written descriptionof all Markush groups used in the appended claims.

Certain embodiments of this invention are described herein, includingthe best mode known to the inventors for carrying out the invention. Ofcourse, variations on these described embodiments will become apparentto those of ordinary skill in the art upon reading the foregoingdescription. The inventor expects skilled artisans to employ suchvariations as appropriate, and the inventors intend for the invention tobe practiced otherwise than specifically described herein. Accordingly,this invention includes all modifications and equivalents of the subjectmatter recited in the claims appended hereto as permitted by applicablelaw. Moreover, any combination of the above-described elements in allpossible variations thereof is encompassed by the invention unlessotherwise indicated herein or otherwise clearly contradicted by context.

Furthermore, numerous references have been made to patents and printedpublications throughout this specification. Each of the above-citedreferences and printed publications are individually incorporated hereinby reference in their entirety.

In closing, it is to be understood that the embodiments of the inventiondisclosed herein are illustrative of the principles of the presentinvention. Other modifications that may be employed are within the scopeof the invention. Thus, by way of example, but not of limitation,alternative configurations of the present invention may be utilized inaccordance with the teachings herein. Accordingly, the present inventionis not limited to that precisely as shown and described.

We claim:
 1. A method for treating an ocular condition comprising thesteps of: providing at least two biodegradable sustained releaseimplants containing latanoprost or a salt thereof; implanting the atleast two biodegradable sustained release implants into the anteriorchamber of an eye; and treating the ocular condition, wherein the atleast two biodegradable sustained release implants release about 100 ngper day of the latanoprost or a salt thereof for a period greater thanabout 1 month.
 2. The method according to claim 1 wherein the ocularcondition is glaucoma.
 3. The method according to claim 1 wherein theocular condition is elevated intraocular pressure.
 4. The methodaccording to claim 1 wherein the sustained release implant releasesabout 70% of the latanoprost or a salt thereof over the first month. 6.The method according to claim 1 wherein the at least two biodegradablesustained release implants comprise about 30% latanoprost or a saltthereof.
 7. The method according to claim 1 wherein the at least twobiodegradable sustained release implants comprise about 5% to about 70%poly(D,L-lactide).
 8. The method according to claim 1 wherein the atleast two biodegradable sustained release implants comprise about 5% toabout 40% poly(DL-lactide-co-glycolide).
 9. The method according toclaim 1 wherein the at least two biodegradable sustained releaseimplants comprise about 5% to about 40% polyethylene glycol.
 10. Themethod according to claim 1 wherein the at least two biodegradablesustained release implants comprise about 30% latanoprost or a saltthereof, 65% poly(D,L-lactide), and 5% polyethylene glycol.
 11. Themethod according to claim 1 wherein the at least two biodegradablesustained release implants comprise about 30% latanoprost or a saltthereof, 65% poly(D,L-lactide), and 5% polyethylene glycol.
 12. Themethod according to claim 1 wherein the at least two biodegradablesustained release implants comprise about 20% latanoprost or a saltthereof, 55% poly(D,L-lactide), 10% poly(DL-lactide-co-glycolide), and5% polyethylene glycol.
 13. The method according to claim 1 wherein theimplanting step is accomplished using an applicator.
 14. The methodaccording to claim 1 wherein the at least two biodegradable sustainedrelease implants are settled out in the inferior angle within 24 hoursof implanting within the anterior chamber.